The goal of this project is to understand the "emmetropization" mechanism that uses visual signals to match the axial length of juvenile eyes to their optical power. Normally this mechanism produces eyes with little refractive error. However, a significant proportion of the population develops refractive errors, particularly myopia, in which the eye is too long for its own optical power. In high myopia, the axial elongation (which is not corrected by optical treatments, including refractive surgery) is a risk factor for glaucoma and retinal detachment, making myopia the 7th leading cause of blindness in the U.S. The emmetropization mechanism has at least three key components: 1) the retina, which detects the amount of defocus, 2) a signaling cascade from the retina, through the choroid to the sclera (the fibrous outer coat of the eye), and 3) fibroblasts in the sclera which respond to retinal signals by regulating the axial length. Our hypothesis is that remodeling of the scleral extracellular matrix controls scleral extensibility, axial elongation and refractive state. In the previous project period, a pattern of changes in mRNA levels was found for specific proteins in tree shrew sclera during the development of myopia induced with monocular form deprivation (MD) and during recovery from induced myopia. In the proposed project period we will expand on this discovery. Specific Aim 1 will examine whether myopia induced with a minus-power lens produces the same pattern of changes in scleral mRNA levels (with a different time-course) as when form deprivation is used. Specific Aim 2 will examine the role played by specific proteins in regulating scleral remodeling. We will measure changes in mRNA and protein levels of a membrane-bound matrix metalloproteinase (MT1- MMP), of MMP-3 and mRNA levels of proteoglycan core proteins (biglycan, aggrecan, lumican and fibromodulin) during the development of minus-lens induced myopia and recovery. Specific Aim 3 will examine the potential role of all-trans-retinoic acid (at-RA) in the signaling cascade to the sclera. We will measure changes in specific mRNAs and changes in scleral extensibility (creep rate) induced in organ culture by physiological levels of at-RA. These experiments will expand our understanding of the visual regulation of axial length and refractive state by describing the molecular events that occur in the sclera of eyes developing myopia. Under- standing the mechanisms regulating scleral remodeling may point the way toward targets for drug intervention to one day control myopia progression.